The extent to which cerebrovascular disease contributes to the frequent cognitive impairment in aging chronic kidney disease (CKD) patients has not been adequately measured. Cognitive impairment and stroke result in medication noncompliance accelerated functional decline, and loss of independence. This longitudinal study will use brain magnetic resonance imaging (MRI) to detect symptomatic and silent incident stroke, a structured cognitive battery to detect impairment, and laboratory values to assess albuminuria and inflammatory markers, to measure the role of stroke and white matter disease and of factors specific to CKD in cognitive impairment. Our long-term goal is to identify factors that increase the risk of cognitive impairment, physical function decline, and loss of independence in aging CKD and hemodialysis subjects. Our central hypothesis is that stroke and white matter disease play large roles in the development of cognitive impairment in these patients, but that microvascular endothelial damage and inflammation are also important contributors to cognitive decline. The rationale for the proposed research is that by defining the role of cerebrovascular disease and other risk factors, we will enable future design of measures to prevent cognitive impairment in CKD patients. The proposed research is relevant to the NIH mission: to develop knowledge to help reduce the burden of disease and disability in humans. Guided by strong preliminary data, we will test our hypothesis through our Specific Aims: 1. (cross-sectional) Determine the baseline prevalence of cognitive impairment (both global and individual domains) in Stage 3b-5 CKD subjects (estimated glomerular filtration rate [eGFR] d 45 ml/min per 1.73 m2) and non-CKD control subjects, and assess risk factors for prevalent severe cognitive impairment in CKD subjects. 2. (Primary Aim, longitudinal) Characterize the association between (a) baseline and incident stroke, white matter disease, eGFR, inflammation, microalbuminuria, dialysis initiation and (b) cognitive decline over 3 years in CKD subjects. 3. (longitudinal) Compare rates of global and domain-specific cognitive decline over 3 years in CKD and non-CKD subjects. We will measure cognitive function using an annual 45-minute cognitive battery in 450 CKD subjects (not on dialysis at baseline) and 150 age- and race-matched non-CKD controls for up to 3 years of follow-up, including the transition zone after hemodialysis initiation for CKD subjects who transition to dialysis. Incident strokes will be detected via annual interviews, participant electronic medical records, and brain MRIs. The approach is innovative by targeting Stage 3b-5 CKD subjects, those most likely to experience cognitive decline, and using brain MRI to detect silent strokes and white matter disease. The research is significant in measuring the extent to which clinical and subclinical cerebrovascular disease and other potentially modifiable risk factors contribute to cognitive decline, to overcome the critical barrier to designing aggressive and timely interventions to prevent cognitive impairment. PUBLIC HEALTH RELEVANCE: This study addresses public health issues that have been largely ignored: the high rate of stroke and cognitive impairment in the aging chronic kidney disease (CKD) population. In 600 subjects (450 with CKD, 150 without), this multiyear project will use interviews, cognitive testing, medical records, brain scans, and laboratory values to study the role of strokes (symptomatic strokes and "silent" strokes) and white matter disease in the cognitive problems that affect CKD patients, including dialysis patients. The long-term goal is to identify factors that increase the risk of cognitive impairment in these patients;the impact of this work will be to enable the design of ways to prevent cognitive impairment, such as improved stroke prevention and dialysis methods.